Protection, restoration, and enhancement of erythropoietin-responsive cells, tissues and organs

Abstract

Methods and compositions are provided for protecting or enhancing an erythropoietin-responsive cell, tissue, organ or body part function or viability in vivo, in situ or ex vivo in mammals, including human beings, by systemic or local administration of an erythropoietin receptor activity modulator, such as an erythropoietin or a modified erythropoietin.

1. A method for protecting, maintaining, enhancing or restoring the function or viability of erythropoietin-responsive mammalian cells, tissues and organs comprising administering to a mammal a pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin having at least one of the following modifications:
 (i) at least one or more chemically modified lysine residues; or 
 (ii) a chemical modification of the N-terminal amino group of the erythropoietin molecule, 
 such that the function or viability of erythropoietin-responsive mammalian cells, tissues and organs is protected, maintained, enhanced or restored without causing an increase in hemoglobin concentration or hematocrit in said mammal. 
 
     
     
       2. The method of  claim 1  wherein said erythropoietin is expressed in an insect or plant cell. 
     
     
       3. The method of  claim 1  wherein said erythropoietin molecule has at least one biotinylated lysine or biotinylated N-terminal amino group. 
     
     
       4. The method of  claim 1  wherein said erythropoietin is glucitolyl lysine erythropoietin or fructosyl lysine erythropoietin. 
     
     
       5. The method of  claim 1  wherein a lysine residue of said erythropoietin is carbamylated. 
     
     
       6. The method of  claim 1  or  5  wherein said mammalian cell or its associated cells, tissues, or organs is selected from the group consisting of bone, liver, kidney, small intestine, testes, ovary, pancreas and endometrial cells, tissues and organs. 
     
     
       7. The method of  claim 1  wherein a lysine residue of said erythropoietin is acylated. 
     
     
       8. The method of  claim 7  wherein a lysine residue of said erythropoietin is acetylated. 
     
     
       9. The method of  claim 7  wherein a lysine residue of said erythropoietin is succinylated. 
     
     
       10. The method of  claim 1  wherein a lysine residue of said erythropoietin is modified by 2,4,6-trinitrobenzenesulfonate sodium or another salt thereof. 
     
     
       11. The method of  claim 1  wherein erythropoietin-responsive cell or tissue is neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, or endometrial cell or tissue. 
     
     
       12. The method of  claim 1  wherein the N-terminal amino group of said erythropoietin is carbamylated. 
     
     
       13. A method for protecting, maintaining, enhancing or restoring the function or viability of erythropoietin-responsive mammalian cell or its associated cells, tissues, or organs, comprising administering to a mammal a pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin,
 wherein said mammalian cell or its associated cells, tissues, or organs is selected from the group consisting of bone, liver, kidney, small intestine, testes, ovary, pancreas and endometrial cells, tissues and organs, and 
 wherein the erythropoietin is carbamylated.